Process for the manufacture of unsaturated ketones of the cyclopentano polyhydro phenanthrene series



FE F l PROCESS FOR THE AGTURE F UNSATURATED KEEONES OF THE CYCLG- ArthurSerini, Berlin N. 65, Heinrich Kiister, Berlin-Charlottenburg, andLothar Strassherger, Berlin-Wilmersdori, Germany, asslgnors, by mesneassignments, to Schering Corporation, Bloomfield, N. 3., a corporationof New Jersey No Drawing. Application re 1; i937, Serial No.

145,824. lin Germany June 2, 11936 21 Claims.

This invention relates to a process for the manufacture of unsaturatedketones of the cyclopentano-polyhydrophenanthrene series from thecorresponding unsaturated secondary alcohols. It

action component during the reaction and in fact always the oxidationproduct is removed, either by physical methods (distillation) or bysecondary chemical change (esters being formed in the case of analdehyde). The latter process therefore relates in particular forexample to the manu- 5 does not allow of the recovery of the oxidationfacture oi unsaturated sterol ketones such as product. In thisconnection it maybe mentioned cholestenone or sitostenone fromcholesterol or that Meerwein and Schmidt refer to their processsitosterol, the manufacture of unsaturated keas a reduction process. Onthe other hand the tones of the pregnanc series, as for examplepregrecovery of the oxidation product from-the renendione, frompregnendiol or pregnenolone and action mixture by distillation takesplace easily the manufacture of unsaturated ketones of the since theboiling points of aldehydes and iretones androsterone series, such asandrostendione or are lower than the boiling points of thecorretestosterone, from dehydro-androsterone or anspending alcohols. Anecessary requirement is drostendiol. however the sufiicient volatilityof the products The oxidation of unsaturated secondary alcois concerned.Nothing is stated regarding the aphols of thecyclopentano-polyhydrophenanthrene plicability of the principle of theexchange of oxiseries to the corresponding unsaturated ketones dationstages to theproduction of non-volatile or is already known, compare forexample: extremely dimcultly'volatile ketorlres suc lhiras those of thecyclopentano-polyhydrop enant en e segi Abdefihalldelu' Berichte 3099"2(1) ries. Apparently if the ketones are not removed lels, Gadke,Kortmg, Annalen 459, 21, Windaus Berichte 39 518 1 l from the reactionit was cons1dered that they hould undergo a secondary chemical changelike Butenandt and Westphal, Berichte 69, pages 443, S i 44% thealdehydes.

According to the present invention the manu- As, oxidising agentschiefly copper oxide and 5 facture of unsaturated ketones of thecyclopenchromic acid are employed; the yields in thesetano-polyhydrophenanthrene series from the corprocesses are moderate andlie between about responding secondary alcohols takes place exand 60%.With the application of chromic acidtraordinari-ly smoothly when thelatter, as metal 1 it is recommended to protect the double bond byalcoholates. or in the presence of other metal addition and subsequentsplitting off of halogen so alcoholates, are treated with an excess of aketone or halogen hydride. The process thereby becomes or aldehyde. Thelarger the excess of ketone or considerably more cumbersome and theyields are aldehyde the more complete the oxidation. not essentiallyhigher but vary between about The ketones of the cyclopentano-polyhy r 4t phenanthrene series, when the oxidation is well These unsaturatedketones' are chiefly subconducted, are obtained in suchadegree of puritystances of valuable physiological properties and that their completepurification is possible by particular therapeutic value. An improvementsimple recrystallisationl If desired, however, of their method ofproduction is therefore of conchemical purification methods can also beem siderable comm porta ployed by causing the reaction product to reactThe process of the present invention renders 40 with ketone reagentssuch assemi-carbazide and 7 possible the production of these unsaturatedkethe like or with hydroxyl reagents for the purtones of thecyclopentano-polyhydrophenanpose of removal of unoxidised alcohol. Thelatthrene series from the corresponding secondary ter can be subjectedto'a further treatment wherealcohols with practically quantitativeyield. It by a: practically quantitative yield of ketone is depends uponan exchange of oxidation stages beobtained. tween the secondary alcoholsand an added alde- The following examples serve to illustrate the hydeor ketone in th presence of t 1 invention without, however, limiting thesame to holates. them. a p The principle of the exchange of oxidationEmmple stages 18 a y o Meerwein and 3.86 grams of cholesterol aredissolved in Schmidt, Annalen 444, 221 and Ponndor grams ofeyclohexanone; this solution is treated Zeitschr. f. angew. Chemie 39,138- with 3.4 grams of aluminium-isopropylate, heated AS these authors ep e it nec ssary for for 4. hours to 100 C. and thereupondistilled-withthe completion of the exchange to remove one re- 5,5steam. The residue is taken'up with ether. After drying'and evaporationof the ether there" re-f 2' mains in quantitative yield thesterolportion, which after washing with a little methanol exhibits amelting point of 78 C. Interaction with semicarbazide yields thesemicarbazone of cholestenone of M. P. 234 C. with 90% yield.

Example 2 'A solution of 3.86 grams of cholesterol and 1 gram of'aluminium-isopropylate in 60' grams of xylene is gradually heated toboiling whereby 0.56 gram of isopropyl-alcohol distils ofi together withabout 25 grams of xylene. The remaining solution of thealuminium-cholosterylate is thereupon treated with 100 grams ofcyclohexanone and heated for 4 hours to 100 C. After steam distillationand ether extraction in quantitative yield'a practically purecholestenone is obtained which can be freed from small quantities ofunchanged cholesterol by treatement with phthalic anhydride in pyridine.

Example 3 3.86 grams of cholesterol are treated with 3 grams ofmagnesium chlorethylate and 100 grams of cyclohexanone in an analogousmanner to that described in Example 1 and worked up.- The yield is thesame as in Example 1.

Example 4 1.6 grams of pregnenol-3eone-20 are dissolved at 120 C. in 50cos. of cyclohexanone and after theaddition of 1.7 gramsof-aluminium-isopropyl- I ate allowed to stand for 10 minutes at thistemperature. After cooling ,the whole i distilled with steam and theresidue taken up with ether. After drying and evaporation of the etherthe oxidation product remains in quantitative yield.

the physiological activity .of the corpus luteum hormone (in theClauberg-Test 1 rabbit unit in 0.7 mg).

- Example 5 1.5 grams of dehydro-androsterone are heated with 1.5 gramsof alumin'ium-isopropylate in ccs. of cyclohexanone for half an'hour toC.,

The reaction mixture is distilled with steam. The residue of the steamdistillation is after cooling treated with dilute sulphuric acid for thedissolving of the aluminium-hydroxide suspension. The

. androstendione separated in solid form is after filtration obtained inquantitative yield and purified by crystallisation from dilute acetone.

Example .6

To a solution heated to 100C. 01 1 gram ofandrostendiol-monobenzoate-l7in 25 grams of -cyclohexanone 0L85 gram of aluminium-isopropylate isadded, the whole is shaken for a short time It exhibits a melting pointof to 127 C. and

dried and the ether evaporated. The ether residue is recrystallised frommethanol,'whereby 0.8 gram of pure testosteronB-benZOate of M. P. 190

and rotation [a]zo is obtained.

Example 7 10 grams of stigmasterol are dissolved in 200 grams of dryacetone, a solution of 12 grams of crystallised aluminium-isopropylatein 300 cos. of

benzene added and the mixture boiled for 10 hours under reflux. Thereaction solution is thereupon shaken several times with dilutesulphuric acid, washed with water, dried with sodium sulphate and thebenzene evaporated in vacuum. The weak yellow colored residue isrecrystallised from methanol and yields stigmastadienone in beautifulcrystals. The melting point of the product which is obtained in a yieldof 5 grams amounts to 107 C.

Emmplel? .3.86 grams of cholesterol and 3.4 grams ofaluminium-isopropylate are dissolved in 120 grams of anhydrousacetophenone. Then the re-' action mixture is heated for 3'hours to 120C. and

finally subjected to steam distillation. Working up takes place as inExample 1. Byerystallisation from acetone 3.3 gramsof cholestenone of M.P. 79 C. are obtained.

Example 9 1.0 gram of androstendiol-monobenzoate-17- is dissolved in 25grams of anhydrous cyclohexanone and the solution heated to 100 G. Then1.0 gram of solid tertiary aluminium-butylate is'added and after 30minutes standing at the said temperature the mixture is worked up as inExample 6. 0.94

gram is obtained of still impure testosterone-benzoate []D ='+.1 49.-

By treatment with phthalic anhydride there can be obtained. therefrom0.86 gram of pure testosterone benzo'ate M. P. 191 C., [a]D +159. I

Example 10 i 1.6 grams of pregnenol-3-one-20 and 1.7 grams ofaluminium-isopropylateare dissolved. in 29.0

until a clear solution is produced and further heated for 30 minutes to100 C. Afterrapid cooling the whole is distilled with steam' untilnothing more passes over and the distillation residue taken up in ether,the ether solution dried grams of acetone and 58.0 grams'of xylene andheated to boiling for 9 hours under a reflux condenser. Then thereaction mixture is poured,

into acidified water whereby the coloured condensation products of theacetone pass into the aqueous phase. The xylene solution is washedseveral times and dried and after evaporation in vacuum leaves 1.54grams of crystalline residue permeated by a small quantity of anoilyreaction product. Byrecrystallisation froin ether there can berecovered therefrom 1.2 grams of corpus luteum hormone of M. P. 128 C.,'[c] ,-=193.1.

Of course, various modifications and; changes in the reactionconditions, etc., may -be made by those skilled in the art in accordancewith the principles set forth herein and in the claims annexed hereto.

What we claim is:

1. Process for the manufacture of unsaturated ketones of thecycl'opentano polyhydro phenanthrene series, which comprises reacting anunsaturated secondary alcohol of the cyclopentano polyhydro phenanthreneseries with a member of the group consisting of aldehydes and ketones inthe presence of a having a, i

CHOH metal alcoholate of an alcohol group, said alcoholate being activeto promote an exchange of oxidation stages.

3. Process according-to claim 1, in which the aldehyde or ketone isemployed in'excess.

dProcess according to claim 1, wherein the metal is bound to thestarting material iii the formof the corresponding alcoholate bytreatment of the starting material in the oxidation.

mixture with a metal alcoholate of another alcohol having a I onongroup.

5. Process according to claim 1," wherein the starting material ispregnenolorie.

6. Process according to claim 1, wherein the starting material is al'l-monoester of androstendim-3,17.

7. Process according to claim 1, wherein the starting material isdehydro-androsteronc.

8. Process for the manufacture of unsaturated ketones of thecyclopentano polyhydro phenanthrone series from the correspondingunsaturated secondary alcohols, which comprises subjecting such alcoholdirectly to the action of a compound of the group consisting ofaldehydes and lretones in the presence of a secondary metal alcoholateactive to promote an exchange of oxidation stages. i

a. Process for the manufacture of unsaturated iretones of thecyclopentano polyhydrophenanthrene series from the correspondingunsaturated secondary alcohols, which comprises subjecting such alcoholto the action of an excess of a com pound from the group consisting ofaldehydes and hetones in the presence of a metal aicoholate of a.monohydric lower aliphatic alcohol having a onou 'threne series from thecorresponding unsaturated secondary alcohols, which comprises subjectingsuch alcohol to the action of an excess of a compound from the groupconsisting of aldehydes and ketones in the presence of a secondaryaluminium alcoholate.

12.7 Process for the manufacture of unsaturated ketones of thecyclopentano polyhydrophenam' throne seriesirom the corresponding i; M

such alcohol to the action of an excess of a compound from the groupconsisting of 'aldehydes and iretones in the presence of a member of thegroup consisting of aluminium and chlor-magnesium alcoholates ofalcohols having a onon group.

13. Process for the manufacture of unsaturated iretones of thecyclopentano polyhydrophenanthrene series from the correspondingunsaturated secondary alcohols, which comprises subjecting such alcoholto the action of an excess of a compound irom the group consisting ofaldehydes and ketones in the presence of aluminium isopropylate.

it. The process of preparing unsaturated keto,

compounds of-the cyclopentano polyhydrophenanthrene series, whichcomprises subjecting the corresponding secondary alcohol to the actionof an excess of a compound selected from the group consisting ofaldehydes and ketones in the presence of an aluminium alcoholate of amonohydric, secondary alcohol.

15. Process for the manufacture of testosterone esters, which comprisesreacting the l'l-monoester of androstendiol with an excess of a ketonein the presence of a secondary aluminium alcoholate.

16. Process for the manufacture of unsaturated ketones of thecyclopentano polyhydro phcnanthrone series, which comprises reactin anunsaturated secondary alcohol of the cyc'lopentano polyhydrophenanthrene series with a member of the group consisting of aldehydcsand lretones in the presence of an aluminium alcoholate of saidsecondary alcohol.

17. Process for the manufacture of unsaturated ketones of thecyclo'pentano polyhydro phenanthrone series, which comprises reacting anunsaturated secondary alcohol of the cyclopentano- I polyhydrophenanthrene series with a member till of the group consisting ofaldehydes and isotopesin the presence of a magnesium alcoholate of saidsecondary alcohol.

18. Process for the manufacture of cholestenone, which comprisesreacting cholesterol with a member of the group consisting of aldehydesand ketones in the presence of aluminium isopro pylate.

19. Process for the manufacture of presnendione," which comprisesreacting pregnenolone with a member of the group consisting ofaldehydes'and ketones whose corresponding alcohols are readily volatile,in the presence of a secondary aluminium alcoholate.

so. Processfor the manufacture of testosterone esters, which comprisesreacting a l'i-mono-ester oi androstendiol with a member of the sroupconsisting of aldehydes and lretones in the presence of aluminiumisopropylate. v V

21. Process for the manufacture of unsaturamd ketones of thecyclopentano polyhydro phenanthrone series, which comprises reacting anunsaturated secondary alcohol of the cyclopentano polyhydro phenanthreneseries in the form. of a metal alcoholatewith a member of the groupconsisting of aldehydes and ketones, said alcoholate being active topromote an exchange oi oxidation stages.

an s. H INR H Kbs'rER. me. 'I L B

